Abstract
Kidins220 (kinase D-interacting substrate of 220 kDa)/ankyrin repeat-rich membrane spanning (ARMS) acts as a signaling platform at the plasma membrane and is implicated in a multitude of neuronal functions, including the control of neuronal activity. Here, we used the Kidins220(-/-) mouse model to study the effects of Kidins220 ablation on neuronal excitability. Multielectrode array recordings showed reduced evoked spiking activity in Kidins220(-/-) hippocampal networks, which was compatible with the increased excitability of GABAergic neurons determined by current-clamp recordings. Spike waveform analysis further indicated an increased sodium conductance in this neuronal subpopulation. Kidins220 association with brain voltage-gated sodium channels was shown by co-immunoprecipitation experiments and Na(+) current recordings in transfected HEK293 cells, which revealed dramatic alterations of kinetics and voltage dependence. Finally, an in silico interneuronal model incorporating the Kidins220-induced Na(+) current alterations reproduced the firing phenotype observed in Kidins220(-/-) neurons. These results identify Kidins220 as a novel modulator of Nav channel activity, broadening our understanding of the molecular mechanisms regulating network excitability.
Highlights
Tight regulation of ion channel activity is essential for neuronal function
We investigated the role of the scaffold protein Kidins220 in the regulation of neuronal excitability using embryonal hippocampal neurons isolated from the previously described Kidins220Ϫ/Ϫ full knock-out mice [16]
We observed higher action potential rising slopes and peak amplitudes in Kidins220Ϫ/Ϫ GABAergic neurons, pointing to an increased Naϩ conductance, which lead us to deduce a misregulation of Nav channels in these cells
Summary
Tight regulation of ion channel activity is essential for neuronal function. Results: The scaffold protein Kidins220 associates with brain voltage-gated sodium channels and modulates their activity. An in silico interneuronal model incorporating the Kidins220-induced Na؉ current alterations reproduced the firing phenotype observed in Kidins220؊/؊ neurons These results identify Kidins220 as a novel modulator of Nav channel activity, broadening our understanding of the molecular mechanisms regulating network excitability. Cumulative evidence from several studies supported the idea that neuronal activity in the hippocampus is reciprocally connected to Kidins220 protein levels, which appear to affect excitatory and inhibitory circuits in opposite ways (4 –7) This connection holds true in the reverse direction, as sustained neuronal activity reduces the amount of Kidins220 protein via transcriptional down-regulation and calpain-dependent protein cleavage [6, 8]. Our results revealed increased excitability of GABAergic neurons in Kidins220 null mice and provided evidence for a functional association of Kidins220 with Nav channels in the brain
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